Process for production of ceophalosporins

ABSTRACT

Cephalosporin and 1-carba(1-dethia)cephalosporin antibiotics substituted in the 3-position with, inter alia, alkyl, alkenyl and alkynyl, are provided via process comprising conversion of a cephalosporin or 1-carba(1-dethia)-3-cephem substituted in the 3-position with halogen or a sulfonyloxy ester with Pd(O) mediated alkylation with organostannanes.

BACKGROUND OF THE INVENTION

This invention relates to β-lactam antibiotics. In particular, itrelates to certain 3-(substituted)-1-carba(dethia)-3-cephems andcephalosporin esters and to a process for the preparation thereof

Among the newer β-lactam antibiotics currently under investigation arethe 1-carba(1-dethia)-3-cephem-4-carboxylic acids. These β-lactamantibiotics provide significant synthetic challenges. Accordingly, oneof the more noteworthy approaches to total synthesis of 1-carba(1-dethia)-3-cephem-4-carboxylic acids is the asymmetric routedescribed by Evans, et al., U.S. Pat. No. 4,665,171. Thus, because thesenewer β-lactam antibiotics provide such synthetic challenges thedevelopment of new processes are of considerable importance.

SUMMARY

7β-Acylamino(and 7β-protected amino)-3-alkyl(and alkenyl, phenyl,substituted phenyl, alkoxymethyl, phenylalkoxymethyl andalkynyl)-1-carba(1-dethia)-3-cephem-4-carboxylic acid esters areproduced in a process comprising the Pd(O) mediated alkyl (alkenyl,phenyl, substituted phenyl, alkoxymethyl, phenylalkoxymethyl,trialkylsilyloxymethyl or alkynyl) transfer from an appropriatelysubstituted organostannane to a 7β-acylamino(or 7β-protectedamino)1-carba(1-dethia)-3-trifluoromethylsulfonyloxy(or mesyloxy,tosyloxy, chloro, bromo or iodo)-3-cephem ester or to the correspondingcephalosporin ester. The process provides certain1-carba(1-dethia)-3-cephem esters (and cephem esters) which, in turn,may be deesterified to provide 1-carba(1-dethia)-3-cephem-4-carboxylicacid (or cephalosporin) antibacterials.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing a compound ofFormula (1): ##STR1## wherein A is a protected amino group or anacylamino group R(CO)--NH--; R₁ is a carboxy-protecting group or abiologically-labile ester; X is sulfur or --CH₂ --; and R₂ is methyl; C₂-C₆ alkenyl; C₂ -C₆ alkynyl; C₁ -C₆ substituted alkyl; C₂ -C₆substituted alkenyl; C₂ -C₆ substituted alkynyl; phenyl, substitutedphenyl; C₁ -C₆ alkyloxymethyl; phenyl-C₁ -C₆ alkyloxymethyl; or tri-(C₁-C₆)alkylsilyloxymethyl; which comprises reacting a compound of Formula(2) ##STR2## wherein A, X and R₁ are as defined above, and R₃ istrifluoromethylsulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy,chloro, bromo or iodo; in an inert solvent in the presence ofpalladium(O) and, when R₃ is trifluoromethanesulfonyloxy,methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of an alkalimetal halide, with a tin transfer reagent of the formula tri(C₁-C₆)alkyl-Sn-R₂ or Sn(R₂)₄, wherein R₂ has the same meanings as definedabove.

The term "alkali metal halide" herein refers to salts such as lithiumchloride, lithium bromide, sodium chloride, sodium bromide and likesalts. Lithium chloride is the preferred alkali metal halide. As oneskilled in the art will appreciate, other halide sources, e.g.,tetraalkylammonium halides such as tetramethyl ammonium chloride may beequally efficacious.

Inert solvents which may be employed include hexane, dimethylformamide,dimethylacetamide and like solvents which are capable of maintainingsubstantially all of the reagents and reactants in solution.

Examples of tin transfer reagents include tetramethylstannane,tetraethylstannane, tri-n-butyl vinyl stannane, tri-n-butyl allylstannane, tri-n-butyl(methoxymethyl)stannane, tri-n-butyl ethynylstannane, tri-n-butyl-[(Z)-1-propene-1-yl]stannane,tri-n-butyl-[(Z)-3,3,3-trifluoro-1-propene-1-yl]stannane,tri-n-butyl(benzyloxymethyl)stannane,tri-n-butyl(2-propyne-1-yl)stannane and the like.

The above process is carried out at a temperature from about -70° C. toabout 150° C., preferably from about 25° C. to about 75° C. undersubstantially anhydrous conditions and preferably in an inert atmospheresuch as a nitrogen or argon atmosphere.

The "tin transfer reagent" of the formula tri(C_(1-C) ₆ alkyl)Sn--R₂ orSn(R₂)₄ is chosen by virtue of the desired R₂ substituent (3-position)in the β-lactam compound. As to the C₁ -C₆ alkyl groups which may appearon the tin transfer reagent, n-butyl is preferred, i.e., tri-n-butyltin-R₂ is the preferred reagent. Further, in some cases, it will bepreferable to use a tin reagent of the formula Sn(R₂)₄ ; for example, ifthe desired R₂ substituent is a simple alkyl such as methyl, Sn(CH₃)₄would be the preferred tin transfer reagent.

The palladium catalyst employed in the process is soluble or partiallysoluble Pd(O) which may be generated in situ or provided directly in theform of a palladium compound such astetrakis-(triphenylphosphine)palladium(O). A reagent useful forgenerating Pd(O) in situ is palladium dichloride diacetonitrilate. Otherwell-known palladium compounds which either exist as Pd(O) or can bereduced to Pd(O) in situ may be utilized if otherwise compatible withthe reactants.

The process is performed by adding the palladium O compound or Pd(O)generating reagents, an alkali metal halide, when R₃ is other than halo,and a tin transfer reagent to a solution of the substrate (2) in aninert solvent. The reaction mixture is typically heated, if necessary,to complete the process. The progress of the reaction may be followed bythin layer chromatography or high-performance liquid chromatographyusing small aliquots of the reaction mixture from time to time. Theresulting 3-substituted 1-carbadethia-3-cephem ester or cephalosporinester (1) may then be recovered from the reaction mixture byconventional isolation techniques. For example, the reaction mixture maybe diluted with a water immiscible solvent such as ethyl acetate, thesolution washed sequentially with dilute acid and bicarbonate and, afterdrying, may be evaporated to provide the product (1) in crude form.Purification may then be effected using conventional methodology, forexample, utilizing recrystallization and/or chromatography, e.g.,high-performance liquid chromatography.

As described above when the process is carried out with a 3-sulfonyloxyderivative, e.g., trifluoromethylsulfonyloxy, the addition of an alkalimetal halide to the reaction mixture is necessary. Conversely, the3-halo substituted starting materials are converted in the processwithout added alkali halide or other halide source.

In a general example of the process, palladium dichloridediacetonitrilate (approximately 0.1 molar equivalent) and lithiumchloride (2.0 molar equivalents) are dissolved in dimethylformamide. Thereaction mixture is then cooled in an ice bath andbenzhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylateis added followed by the stannane (CH₃ CH₂ CH₂ CH₂)₃ Sn--C.tbd.C--CH₃.After the reaction is complete, conventional isolation and purificationtechniques providebenzhydryl-7β-phenoxyacetyl-1-carba(1-dethia)-3-(1-propynyl)-3-cephem-4-carboxylatein good yield.

Preferred starting materials (2) include compounds wherein R₃ is bromo,iodo or trifluoromethanesulfonyloxy.

Some examples of the 3-substituted cephalosporins and1-carba(1-dethia)-3-cephems produced by the process includep-nitrobenzyl-7β-phenoxyacetylamino-3-(cis-1-propenyl)-3-cephem-4-carboxylate;p-nitrobenzyl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-(cis-1-propenyl)-3-cephem-4-carboxylate;benzhydryl-7β-phenoxyacetylamino-3-vinyl-3-cephem-4-carboxylate;benzhydryl-7β-phenylacetylamino-1-carba(1-dethia)-3-vinyl-3-cephem-4-carboxylate;p-nitrobenzyl-7β-phenoxyacetylamino-3-(benzyloxy)methyl-3-cephem-4-carboxylate;andp-nitrobenzyl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-(benzyloxy)methyl-3-cephem-4-carboxylate;benzhydryl7β-t-butyloxycarbonylamino-1-carba(1-dethia)-3-vinyl-3-cephem-4-carboxylate;p-nitrobenzyl7β-t-butyloxycarbonylamino-1-carba(1-dethia)-3-vinyl-3-cephem-4-carboxylate;benzhydryl7β-t-butyloxycarbonylamino-1-carba(1-dethia)-3-(cis)-1-propene-1-yl)-3-cephem-4-carboxylate;andp-nitrobenzyl-7β-t-butyloxycarbonylamino-1-carba(1-dethia)-3-(cis)-(1-propene-1yl)-3-cephem-4-carboxylate.

The 1-carba-3-trifluoromethylsulfonyloxy esters of Formula (2) which areused as the starting materials in the process may be prepared by themethod of Evans, et al., U.S. Pat. No. 4,673,737. The other startingmaterials of Formula (2) wherein R₃ is tosylate, mesylate or halo arelikewise known compounds synthesized by known methodology.

In Formula (1), when A is an acylamino group R(CO)NH--, R is hydrogen;C₁ -C₆ alkyl, C₁ -C₆ alkyl substituted by cyano, carboxy, halogen,amino, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio, or trifluoromethylthio; a phenylor substituted phenyl group represented by the formula ##STR3## whereina and a' independently are hydrogen, halogen, hydroxy, C₁ -C₄ alkoxy, C₁-C₄ alkanoyloxy, C₁ -C₄ alkyl, C₁ -C₄ alkylthio, amino, mono- or di(C₁-C₄ alkyl)amino, C_(1-C) ₄ alkanoylamino, C₁ -C₄ alkylsulfonylamino,carboxy, carbamoyl, hydroxymethyl, aminomethyl, or carboxymethyl; agroup represented by the formula ##STR4## wherein a and a' have the samemeanings as defined above, Z is O or S, and m is 0 or 1; aheteroarylmethyl group represented by the formula

    R.sup.1 --CH.sub.2 --

wherein R¹ is thienyl, furyl, benzothienyl, benzofuryl, indolyl,triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,and such heteroaryl groups substituted by amino, hydroxy, halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylsulfonylamino; a substitutedmethyl group represented by the formula ##STR5## wherein R² iscyclohex-1,4-dienyl, or a phenyl group or substituted phenyl grouprepresented by the formula ##STR6## wherein a and a' have the abovedefined meanings, or R² is R¹ as defined above, and Q is hydroxy, C₁ -C₄alkanoyloxy, carboxy, sulfo, or amino; or R is a keto group or anoximino-substituted group represented by the formulae ##STR7## whereinR³ is R¹ or R² as defined above and R⁴ is hydrogen, C₁ -C₄ alkyl, or acarboxy-substituted alkyl or cycloalkyl group represented by the formula##STR8## wherein b and b' independently are hydrogen, or C₁ -C₃ alkyl,and b and b' when taken together with the carbon to which they arebonded form a 3- to 6-membered carbocyclic ring, and R⁵ is hydroxy, C₁-C₄ alkoxy, amino, C₁ -C₄ alkylamino, or di(C₁ -C₄ alkyl)amino and n is0 or 1.

In the above definitions, C₁ -C₆ alkyl refers to the straight andbranched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, and like alkylgroups; C₁ -C₆ alkyl substituted by cyano refers to cyanomethyl,cyanoethyl, 4-cyanobutyl, and the like; C₁ -C₆ alkyl substituted bycarboxy refers to such groups as carboxymethyl, 2-carboxyethyl,2-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, and the like; C₁ -C₆alkyl substituted by halogen refers to chloromethyl, bromomethyl,2-chloroethyl, 1-bromoethyl, 4-chlorobutyl, 4-bromopentyl,6-chlorohexyl, 4-fluorobutyl, 3-fluoropropyl, fluoromethyl, and thelike; C₁ -C₆ alkyl substituted by amino refers to such groups as2-aminoethyl, aminomethyl, 3-aminopropyl and 4-aminobutyl; C₁ -C₆ alkylsubstituted by C₁ -C₄ alkoxy refers to methoxymethyl, 2-methoxyethyl,2-ethoxyethyl, ethoxymethyl, 3-propoxypropyl, 3-ethoxybutyl,4-t-butyloxybutyl, 3-methoxypentyl, 6-methoxyhexyl, and like group; C₁-C₆ alkyl substituted by C₁ -C₄ -alkylthio refers to such groups as forexample methylthiomethyl, 2-methylthioethyl, 2-ethylthiopropyl,4-methylthiobutyl, 5-ethylthiohexyl, 3-t-butylthiopropyl, and likegroups; C₁ -C₆ alkyl substituted by trifluoromethyl is exemplified by2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andthe like; and C₁ -C₆ alkyl substituted by trifluoromethylthio refers to,for example, trifluoromethylthiomethyl, 2-trifluoromethylthioethyl,2-trifluoromethylthiopropyl, 4-trifluoromethylthiobutyl,5-trifluoromethylthiohexyl, and like C₁ -C₆ alkyl substituted groups.

When in Formula (1) R is a substituted phenyl group wherein thesubstituent(s) are represented by a and a', examples of such groups arehalophenyl such as 4-chlorophenyl, 3-bromophenyl, 2-fluorophenyl,2,4-dichlorophenyl, and 3,5-dichlorophenyl; hydroxyphenyl such as2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl,and 3,4-dihydroxyphenyl; alkoxyphenyl, such as 2,6-dimethoxyphenyl,4-methoxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl,4-t-butyloxyphenyl, 4-methoxy-3-ethoxyphenyl, and 4-n-propoxyphenyl;alkanoyloxyphenyl such as 2-acetoxyphenyl, 4-propionoxyphenyl,4-formyloxyphenyl, 4-acetoxyphenyl, 3-butyryloxyphenyl, and3-acetoxyphenyl; alkylphenyl such as 4-methylphenyl, 2-methylphenyl,2,4-dimethylphenyl, 3-t-butylphenyl, 4-ethylphenyl,4-ethyl-3-methylphenyl, and 3,5-dimethylphenyl; alkylthiophenyl such as4-methylthiophenyl, 3-n-butylthiophenyl, 2-ethylthiophenyl,3,4-dimethylthiophenyl, and 3-n-propylthiophenyl; aminophenyl such as2-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl, and 3-aminophenyl;alkanoylamino such as 2-acetylamino, 4-acetylamino, 3-propionylamino,and 4-butyrylamino; alkylsulfonylamino such a 3-methylsulfonylamino,4-methylsulfonylamino, 3,5-(dimethylsulfonylamino)phenyl,4-n-butylsulfonylaminophenyl, and 3-ethylsulfonylaminophenyl;carboxyphenyl such as 2-, 3-, or 4-, carboxyphenyl, 3,4-dicarboxyphenyl,and 2,4-dicarboxyphenyl; carbamoylphenyl such as 2-carbamoylphenyl,2,4-dicarbamoylphenyl, and 4-carbamoylphenyl; hydroxymethylphenyl suchas 4-hydroxymethylphenyl and 2-hydroxymethylphenyl; aminomethylphenylsuch as 2-aminomethylphenyl and 3-aminomethylphenyl; and carboxyphenylsuch as 2-carboxymethylphenyl, 4-carboxymethylphenyl, and3,4-dicarboxymethylphenyl; and the substituted phenyl groups bearingdifferent substituents such as 4-chloro-3-methylphenyl,4-fluoro-3-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl,4-hydroxy-3-chlorophenyl, 4-hydroxy-3-methylphenyl,4-ethyl-3-hydroxyphenyl, 4-methoxy-3-hydroxyphenyl,4-t-butyloxy-2-hydroxyphenyl, 4-acetylamino-3-methoxyphenyl,3-amino-4-ethylphenyl, 2-aminomethyl-4-chlorophenyl,2-hydroxymethyl-3-methoxyphenyl, 2-hydroxymethyl-4-fluorophenyl,2-acetoxy-4-aminophenyl, 4-acetoxy-3-methoxyphenyl,3-isopropylthio-4-chlorophenyl, 2-methylthio-4-hydroxymethylphenyl,4-carboxy-3-hydroxyphenyl, 4-ethoxy-3-hydroxyphenyl,4-methylsulfonylamino-2-carboxyphenyl, 4-amino-3-chlorophenyl, and2-carboxymethyl-4-hydroxyphenyl.

Examples of RCONH-- groups of Formula (1) wherein R is a grouprepresented by the formula ##STR9## with m=0 are: phenylacetyl,4-hydroxyphenylacetyl, 4-chlorophenylacetyl, 3,4-dichlorophenylacetyl,4-methoxyphenylacetyl, 3-ethoxyphenylacetyl, 2-aminomethylphenylacetyl,3-carboxyphenylacetyl, 4-acetoxyphenylacetyl, 3-aminophenylacetyl, and4-acetylaminophenylacetyl; and with m=1 and Z=O, phenoxyacetyl,4-chlorophenoxyacetyl, 4-fluorophenoxyacetyl, 3-aminophenoxyacetyl,3-hydroxyphenoxyacetyl, 2-methoxyphenoxyacetyl,2-methylthiophenoxyacetyl, 4-acetylaminophenoxyacetyl,3,4-dimethylphenoxyacetyl, and 3-hydroxymethylphenoxyacetyl; and withm=1 and Z=S, phenylthioacetyl, 4-chlorophenylthioacetyl,3,4-dichlorophenylthioacetyl, 2-fluorophenylthioacetyl,3-hydroxyphenylthioacetyl, and 4-ethoxyphenylthioacetyl.

Examples of R¹ --CH₂ CONH-groups of Formula (1) wherein R¹ is aheteroaryl group are: 2-thienylacetyl, 3-thienylacetyl, 2-furylacetyl,2-benzothienylacetyl, 2-benzofurylacetyl, indol-2-ylacetyl,1H-tetrazol-1-ylacetyl, oxazol-2-ylacetyl, oxazol-4-ylacetyl,thiazol-4-ylacetyl, 2-aminothiazol-4-ylacetyl,1,3,4-oxadiazol-2-ylacetyl, 1,3,4-thiadiazol-2-ylacetyl,5-ethyl-1,3,4-thiadiazol-2-ylacetyl, and like heteroaryl groupsoptionally substituted by amino, C₁ -C₄ alkylsulfonylamino, hydroxy,halo, C₁ -C₄ alkyl or C₁ -C₄ -alkoxy groups.

Examples of RCONH-- groups of Formula (1) compounds wherein R is asubstituted methyl group represented by the formula R² --CH(Q)-- and Qis amino, carboxy, hydroxy, or sulfo, are 2-carboxy-2-phenylacetyl,2-carboxy-2-(4-hydroxyphenyl)acetyl, 2-amino-2-phenylacetyl,2-amino-2-(4-hydroxyphenyl)acetyl,2-amino-2-(3-chloro-4-hydroxyphenyl)acetyl,2-amino-2-(cyclohex-1,4-dien-1-yl)acetyl, 2-hydroxy-2-phenylacetyl,2-formyloxy-2-phenylacetyl, 2-sulfo-2-phenylacetyl,2-sulfo-2-(4-methylphenyl)acetyl, and2-acetoxy-2-(3-hydroxyphenyl)acetyl, 2-amino-2-(2-thienyl)acetyl,2-amino-2-(3-benzothienyl)acetyl, 2-amino-2-(1H-tetrazol-1-yl)acetyl,2-hydroxy-2-(1,3,4-thiadiazol-2-yl)acetyl,2-amino-2-(2-aminothiazol-4-yl)acetyl, 2-carboxy-2-(2-thienyl)acetyl,2-carboxy-2-(benzothien-2-yl)acetyl, and2-hydroxy-2-(benzofur-2-yl)acetyl.

Examples of RCONH-- acyl groups of the compounds represented by Formula(1) when R is a keto group or an oximino-substituted group representedby the formulae ##STR10## are the keto groups 2-oxo-2-phenylactyl,2-oxo-2-(2-thienyl)acetyl, 2-oxo-2-(2-aminothiazol-4-yl)acetyl; andoximino-substituted groups 2-phenyl-2-methoxyiminoacetyl,2-(2-thienyl)-2-ethoxyiminoacetyl, 2-(2-furyl)-2-methoxyiminoacetyl,2-(2-benzothienyl)-2-carboxymethoxyiminoacetyl,2-(2-thienyl)-2-(2-carboxyethoxy)iminoacetyl,2-(2-amino-1,2,4-thiadiazol-4-yl)-2-methoxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl,2-(2-chlorothiazol-4-yl)-2-methoxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-yl)oxyiminoacetyl,2-(2-aminothiazol-4-yl)-2-(2-carbamoylprop-2-yl)oxyiminoacetyl, and2-(5-amino-1,3,4-thiadiazol-2-yl)-2-methoxyiminoacetyl.

The starting material (2) desirably has any free amino or carboxyfunctions which may be present in the R(CO) groups in protected form,e.g., protected with an R₁ protecting group or a protected amino groupas defined below.

The carboxy-protecting group R₁ is a conventional carboxy-blocking groupused in the β-lactam antibiotic art and serves the function of blockingthe acidic carboxy group while reactions are carried out at other sitesin the molecule. Such groups are used for the temporary protection orblocking of the carboxy group. Examples of such groups are t-butyl,haloalkyl groups, e.g. 2,2,2-trichloroethyl, 2-iodoethyl, benzyl,substituted benzyl, e.g. 4-nitrobenzyl and 4-methoxybenzyl,diphenylmethyl, trialkylsilyl or mixed alkylarylsilyl groups, e.g.trimethylsilyl, triethylsilyl, dimethylphenylsilyl,β-trimethylsilylethyl, and β-methylsulfonylethyl, Preferredcarboxy-protecting groups are 4-nitrobenzyl and diphenylmethyl.

The term "biologically-labile ester" refers to those biologically activeester forms which induce increased blood levels and prolong the efficacyof the corresponding non-esterified forms of the compounds. Such estergroups include the lower alkoxymethyl groups, for example,methoxymethyl, ethoxymethyl, iso-propoxymethyl and the like; the α-(C₁to C₄)-alkoxyethyl groups, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl and the like; the2-oxo-1,3-dioxolen-4-ylmethyl groups, such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl,5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl and the like; the C₁ to C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl and the like; the acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl and the like; theethoxycarbonyl-1-methyl group; the α-acyloxy-α-substituted methylgroups, for example, α-acetoxyethyl; the 3-phthalidyl or5,6-dimethylphthalidyl groups; the 1-(C₁ to C₄alkyloxycarbonyloxy)eth-1-yl groups such as the1-(ethoxycarbonyloxy)eth-1-yl group; and the 1-(C₁ to C₄alkylaminocarbonyloxy)eth-1-yl groups such as the1-(methylaminocarbonyloxy)eth-1-yl group.

Protected amino groups represented by A in Formulae (1) and (2) are theconventional protecting or blocking groups attached to an amino group,which are used in the β-lactam antibiotic art for the temporaryprotection of the amino group function while reactions at other sites inthe molecule are carried out. Examples of suitable protecting groups areformyl, trichloroacetyl, tribromoacetyl, trityl, an alkyl, cycloalkyl,or aryloxycarbonyl group such as ethoxycarbonyl, t-butyloxycarbonyl,trichloroethoxycarbonyl, cyclopentylcarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, and diphenylmethoxycarbonyl; allyloxycarbonyl,a bicyclooxycarbonyl group such as adamantyloxycarbonyl orbicycloheptyloxycarbonyl; an enamine group such as that formed from afree amine and methylacetoacetate or ethylacetoacetate; or otherconventional amino-protecting group. Preferred protected amino groups Aare represented by the formula ##STR11## wherein R°₁ is C₁ -C₄ -alkyl;C₃ -C₇ cycloalkyl, benzyl, nitrobenzyl, halobenzyl or methoxybenzyl.Preferred protected amino groups are benzyloxycarbonylamino,p-nitrobenzyloxycarbonylamino, and t-butyloxycarbonylamino.

The 3-substituted esters (1) obtained in the process of this inventionmay be deesterified to provide the free C₄ carboxylic acid antibiotics.Accordingly, the 7-substituent may be changed or derivatized to provideother β-lactam antibiotics.

In a preferred aspect of the process, A is t-butoxycarbonylamino,phenoxyacetylamino or phenylacetylamino, and X is carbon.

In a further preferred aspect of the process, A ist-butoxycarbonylamino, phenoxyacetylamino, phenylacetylamino; X issulfur; and R₂ is (cis)prop-1-ene-1-yl.

As used herein, the term C₂ to C₆ alkenyl refers to straight andbranched olefins. Examples of the term C₂ to C₆ alkenyl include ethenyl,1-propenyl, 2-propene-1-yl, 1-butene-1-yl, 2-butene-1-yl, 3-butene-1-yl,1-pentene-1-yl, 2-pentene-1-yl, 3-pentene-1-yl, 4-pentene-1-yl,1-hexene-1-yl, 2-hexene-1-yl, 3-hexene-1-yl, 4-hexene-1-yl,5-hexene-1-yl, isopropene-1-yl, isobutenyl, isopentenyl, isohexenyl andthe like.

A preferred subgroup of the term C₂ to C₆ alkenyl is a group of theformula C₃ to C₆ alkenyl.

As used herein, the term C₂ to C₆ substituted alkenyl refers to a C₂ toC₆ alkenyl group substituted by one or more halogen, hydroxy, protectedhydroxy, nitro or trihalomethyl groups. It will, of course, beappreciated that a free hydroxy group may need to be protected duringthe course of the process as taught herein. Preferred C₂ to C₆substituted alkenyl groups are (Z)-3,3,3-trifluoro-1-propene-1-yl and(Z)-1-propene-1-yl.

As used herein, the term C₂ to C₆ alkynyl refers to straight andbranched acetylenic groups. Examples of the term C₂ to C₆ alkynylinclude ethynyl, 1-propyne-1-yl, 2-propyne-1-yl, 1-butyne-1-yl,2-butyne-1-yl, 3-butyne-1-yl, 1-pentyne-1-yl, 2-pentyne-1-yl,3-pentyne-1-yl, 4-pentyne-1-yl, 1-hexyne-1-yl, 2-hexyne-1-yl,3-hexyne-1-yl, 4-hexyne-1-yl, 5-hexyne-1-yl, 2-methyl-2-propyne-1-yl,2-methyl-4-propyne-1-yl, 2-methyl-3-pentyne-1-yl, 2-methyl-3-butyne-1-yland the like.

As used herein, the term C₂ to C₆ substituted alkynyl refers to a C₂ toC₆ alkynyl group substituted by one or more halogen, hydroxy, protectedhydroxy, nitro or trihalomethyl.

As used herein, the term substituted phenyl denotes the same groups asdefined hereinabove for the term R.

Examples of the term C₁ to C₆ alkyloxymethyl include methyloxymethyl,ethyloxymethyl, n-propyloxymethyl, n-butyloxymethyl, n-pentyloxymethyl,n-hexyloxymethyl, isopropyloxymethyl, isobutyloxymethyl,isopentyloxymethyl, isohexyloxymethyl and the like.

Examples of the term phenyl C₁ to C₆ alkyloxymethyl includebenzyloxymethyl, (2-phenyl)ethyloxymethyl, (3-phenyl)-n-propyloxymethyl,(4-phenyl)-n-butyloxymethyl, (5-phenyl)-n-pentyloxymethyl,(6-phenyl)-n-hexyloxymethyl, (2-phenyl)(2-methyl)ethyloxymethyl,(3-phenyl)(3-methyl)-n-propyloxymethyl and the like.

In a further aspect of the present invention, there are providedcompounds of Formula (3): ##STR12## wherein A' is amino or A as definedabove for Formula (1); R₂ ' is C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₂ toC₆ substituted alkenyl, C₂ to C₆ substituted alkynyl or a group of theformula --CH₂ --O--SiR'R"R'", wherein R', R" and R'" are the same ordifferent and are C₁ to C₆ alkyl; and R₁ ' is hydrogen, acarboxy-protecting group, a biologically-labile ester; or, when R₁ ' ishydrogen, a pharmaceutically-acceptable salt thereof.

Preferred compounds are represented by Formula (3), wherein R₂ ' is C₂-C₆ alkenyl group. Particular preferred groups are represented when R₂ 'is vinyl or a propenyl group of the formula ##STR13## wherein R₄ ismethyl or trihalomethyl. An especially preferred embodiment of thepresent invention are the compounds of Formula (3) wherein R₂ ' is agroup of the formula ##STR14## and R₄ is trifluoromethyl.

Compounds of Formula (3) wherein R₁ ' is hydrogen can be prepared bydeesterification of the corresponding compound of Formula (2), whereinR₁ is a carboxy-protecting group, by utilization of conventionalmethodology.

Among the preferred compounds are those wherein A is R(C)--NH-- and R is##STR15## especially where Q is amino and R² is phenyl, hydroxyphenyl orcyclohexadienyl. An especially preferred compound is7β-phenylglycylamino-3-(Z)(2-propenyl)-1-carba(1-dethia)-3-cephem-4-carboxylicacid.

The 1-carbacephalosporins provided by the invention form salts withsuitable bases, in particular, the pharmaceutically-acceptable,non-toxic salts. The C-4 carboxy group of the 1-carbacephalosporin canform salts with the alkali and alkaline earth metal hydroxides,carbonates and bicarbonates. Examples of suchpharmaceutically-acceptable salts are the sodium, potassium, calcium andmagnesium salts. Salts also may be formed with amines such asdibenzylamine, cyclohexylamine, triethylamine, ethanolamine,di-ethanolamine and like amines. Likewise, when the 1-carbacephalosporinis substituted by two or more carboxy groups, di- and tri-salts areobtained by conventional salt-forming methods.

1-Carbacephalosporin compounds represented by Formula (3) which bear anamino group substituent in the 7-position side chain also form saltswith suitable acids to provide the antibiotics aspharmaceutically-acceptable salts. Examples of suitable acids arehydrochloric, hydrobromic, sulfuric and phosphoric.

The pharmaceutically-acceptable, non-toxic salts are useful forms of theantibiotics for preparing antibiotic formulations.

This invention also provides a method for treating infectious diseasesin man and animals and pharmaceutical formulations suitable foradministration in the treatment method. The therapeutic method of thisinvention comprises administering to a man or other animals anantibiotically effective non-toxic dose of a compound represented byFormula (1) wherein R₂ is hydrogen or a pharmaceutically acceptable saltor biologically labile ester thereof.

An antibiotically effective amount is an amount between about 25 mg andabout 2 grams. The compound, salt or ester may be administered in asingle dose or in multiple doses throughout the day. Treatment maycontinue for a week to ten days or longer depending upon the duration ofthe infection. The particular dose and regimen can depend on suchfactors as the weight and age of the patient, the particular causativeorganism, the severity of the infection, the general health of thepatient, and the tolerance of the individual to the antibiotic.

The 1-carbacephalosporins may be administered parenterally, orally,subcutaneously or rectally. As with other β-lactam antibiotics, themethod of this invention may be used prophylactically to preventinfections after exposure or before possible exposure, e.g.,preoperatively. The antibiotic 1-carbacephalosporins may be administeredby conventional methods, e.g., in capsules, tablets, by syringe, or byintravenous drip.

The pharmaceutical formulations of the invention comprise anantibiotically effective non-toxic amount of a 1-carbacephalosporinrepresented by Formula (1) wherein R₂ is hydrogen, a pharmaceuticallyacceptable non-toxic salt or biologically labile ester thereof, and apharmaceutical carrier.

Formulations for oral administration include capsules, tablets, lozengesand liquid suspensions. The antibiotic or a salt or ester thereof in theform of a dry powder is encapsulated in gelatin capsules for oral use.The antibiotic may also be blended with an excipient, e.g., astabilizer, prior to filling. Capsules may contain between about 100 mgand about 500 mg to provide unit dosage formulatins.

Tablets containing between about 100 mg and 500 mg of the antibiotic ora salt or ester thereof are formulated by conventional means and maycontain in addition a binding agent, disintegrating agent, stabilizingagent, antioxidant, etc.

Liquid preparations of the antibiotic may be prepared for infant andgeriatric use. Pediatric suspensions are formulated with the antibioticoral excipients such as suspending agents, flavoring agents, stabilizersand the like. Solutions of the antibiotics likewise may be formulatedwith solubilizing agents, flavoring agents, sugar, water, etc.

Parenteral formulations of the antibiotics for injection are formulatedwith Water-for-Injection, Ringer's solution, physiological saline orglucose solution. The antibiotic also may be administered in anintravenous fluid by the drip method.

For parenteral use the antibiotic, a salt or biologically labile esterthereof, is made up preferably in dry crystalline powder form or as alyophilized powder and filled into vials. Such vials contain betweenabout 100 mg and about 2 grams of antibiotic per vial.

The following Experimental Section provides further examples of thevarious aspects of the present invention but is not to be construed aslimiting the scope therefor.

EXPERIMENTAL SECTION Preparation 1

Palladium dichloride diacetonitrilate

A 20 g sample of palladium dichloride was dissolved in 375 ml of CH₂ CN,stirred under N₂ and heated to reflux for 0.5 h. The insoluble materialwas filtered off and the filtrate set aside. The title compoundcrystallized upon standing from the above filtrate. Filtration followedby drying at room temperature under reduced pressure provided 7.23 g ofthe title compound.

EXAMPLE 1p-Nitrobenzyl-7β-phenoxyacetylamino-3-vinyl-3-cephem-4-carboxylate

To a solution of 1 ml of dimethylformamide was added 282 g (0.5 mmol) ofp-nitrobenzyl7β-phenoxyacetylamino-3-methanesulfonyloxy-3-cephem-4-carboxylate, 87 mg(1.00 mmol) of lithium bromide and 6.5 mg (0.025 mmol) of palladiumdichloride diacetonitrilate and the solution stirred under N₂. Thereaction mixture was treated with 16 μl (0.55 mmol) of tri-n-butyl vinyltin, stirred for 16 h, and then treated with an additional 6 mg ofpalladium dichloride diacetonitrilate. After an additional 3 h ofstirring, the reaction mixture was diluted with water and extracted withethyl acetate. The ethyl acetate portion was then washed (2×) with waterand concentrated in vacuo. The crude residue was then dissolved inacetonitrile and washed (3×) with hexane. Removal of solvent in vacuo,followed by liquid chromatography (gradient elution: 3% ethylacetate/CH₂ Cl₂ to 5% ethyl acetate/CH₂ Cl₂) provided 130 mg of thetitle compound.

NMR (300 MHz, TMS, CDCl₃): 3.55 (d, 1H), 4.60 (s, 2H); 5.05 (d, 1H);5.40 (d, 1H); 5.53 (d, 1H); 5.92 (d, of d, 1H); 6.94 (br d, 2H); 7.0-7.4(m, 7H); 7.59 (d, 2H); 8.22 (d, 2H).

PREPARATION 2 (Z)-tri-n-Butyl-(1-propenyl)stannane (Reference: J. F.Normant, Org. Syn., Vol. 62, page 1).

A 4.32 g (0.021 mole) sample of CuBr.(CH₃)₂ S was dissolved in 40 ml ofanhydrous diethyl ether and cooled to -50° C. under argon. Next, a 78.4ml sample of a 0.51 molar solution of methyl lithium (in diethyl ether)was added dropwise (via syringe) at such a rate so as to maintain thetemperature of the reaction mixture at or below -20° C. After additionwas complete, the reaction was stirred at -30° C. for 20 minutes andthen treated (under the reaction mixture surface) with a constant streamof acetylene for 15 minutes, while maintaining the temperature of thereaction mixture at or below -25° C. Stirring is then continued for anadditional 25 minutes, followed by saturation of the reaction mixturewith argon to remove unreacted acetylene.

The resulting cuprate solution was then cooled to -60° C. and maintainedbetween -50° C. and -60° C. while 13.0 ml (15.62 mg; 0.048 moles, 1.2molar equivalents) of tri-n-butyl tin chloride (dissolved in 30 ml ofanydrous diethyl ether) was added. The reaction mixture was then allowedto warm to room temperature overnight.

The resulting reaction mixture was cooled, quenched with saturated NH₄Cl solution and filtered through Celite. The inorganic layer was washedwith hexane and the combined organic phases were washed sequentiallywith saturated NH₄ Cl solution and brine, dried over anhydrous NH₄ SO₄,filtered and concentrated in vacuo. The resulting crude material wasdistilled through a Vigreaux column (91°-94° C./0.25 mm Hg) to provide3.5 g of the title compound as a clear oil.

EXAMPLE 2p-Nitrobenzyl-7β-phenoxyacetylamino-3-(cis-1-propenyl)-3-cephem-4-carboxylate

A 274 mg (0.5 mmol) sample ofp-nitrobenzyl-7β-phenoxyacetylamino-3-bromo-3-cephem-4-carboxylate and8.5 mg (0.032 mmol) sample of palladium dichloride diacetonitrilate weredissolved in 1 ml of anhydrous dimethylformamide. Under N₂, the reactionmixture was treated with tri-n-butyl, cis(1-propenyl)stannane andstirred at room temperature for 1 h. At this point, no reaction hadoccurred, so another 8.5 mg of palladium dichloride diacetonitrilate wasadded and the reaction mixture heated slightly. The reaction mixture wasthen allowed to stir overnight.

The resulting crude product mixture was poured into water and extractedwith (1:1) ethyl acetate/diethyl ether. The resulting organic phase wasthen washed with water and concentrated in vacuo. The crude product wasdissolved in CH₃ CN and extracted with hexane (3×). Removal of solventin vacuo, followed by flash chromatography over silica (5% ethylacetate/CH₂ Cl₂ as eluent) provided 162 mg (64% yield) of the titlecompound.

NMR (300 MHz, TMS, CDCl₃) δ: 1.60 (br d, 3H); 3.38 (d, 1H); 3.55 (d,1H); 4.57 (s, 2H); 5.10 (d, 1H); 5.25-5.40 (m, 3H); 5.66-5.77 (m, 1H);5.90 (d of d, 1H); 6.17 (br d, 1H); 6.92 (d, 2H); 7.03 (t, 1H); 7.2-7.4(m, 3H); 7.60 (d, 2H); 8.21 (d, 2H).

EXAMPLE 3p-Nitrobenzyl-7β-phenoxyacetylamino-3-ethenyl-3-cephem-4-carboxylate

In a manner analogous to that of Example 3 (i.e., tri-n-butylethenylstannane was used as the tin transfer reagent), the title compound wasproduced from the 3-bromo-3-cephem ester.

NMR (300 MHz, TMS, CDCl₃) δ: 3.55 (d, 1H); 4.60 (s, 2H); 5.05 (d, 1H);5.40 (d, 1H); 5.53 (d, 1H); 5.92 (d of d, 1H); 6.94 (br d, 2H); 7.0-7.4(m, 7H); 7.59 (d, 2H); 8.22 (d, 2H).

EXAMPLE 4Benzyhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-methyl-3-cephem-4-carboxylate

A 2 mg (0.008 mmol) sample of palladium dichloride diacetonitrilate and13 mg (0.318 mmol) of lithium chloride were dissolved in 0.26 ml ofdimethylformamide. To this solution was added a 10 mg (0.159 mmol)sample of benzyhydryl7β-phenoxyacetylamino-1-carba(1-dethia)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylatefollowed by 31 mg (24 μl; 0.175 mmol) of tetramethyl stannane. Thereaction mixture was then stirred under N₂ for 10 minutes. At that time,the reaction mixture was treated with an additional 2 mg of palladiumdichloride diacetontrilate (repeated after 10 additional minutes).Finally, an additional 2.0 molar equivalents of tetramethyl stannane and2 mg of palladium dichloride diacetonitrilate were added and thereaction mixture was heated to 35° C. Shortly thereafter the reactionwas complete. The crude product mixture was diluted with CH₃ CN andwashed (3×) with hexane. The CH₃ CN solution was then evaporated invacuo and the crude product redissolved in ethyl acetate/diethyl ether(1:1). The resulting solution was then washed (3×) with water, filteredand evaporated in vacuo. The crude product was chromatographed oversilica gel (5% ethyl acetate/CH₂ Cl₂ as eluent) to provde 55 mg (70%yield) of the title compound.

NMR (300 MHz, CDCl₃): 1.30-1.44 (1H, m); 1.70-1.80 (1H, m); 1.94 (3H,s); 2.14-2.27 (2H, m); 3.74-3.80 (1H, m); 4.50 (2H, s); 5.30-5.37 (1H,m); 6.80-6.94 (2H, m); 6.94 (1H, t); 7.14-7.47 (14H, m).

EXAMPLE 5Benzhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-vinyl-3-cephem-4-carboxylate

A 2.00 g (3.17 mmol) sample of benzhydryl7β-phenoxyacetylamino-1-carba(1-dethia)-3-methanesulfonyloxy-3-cephem-4-carboxylate,41 mg (0.16 mmol) of palladium dichloride diacetonitrilate, and 295 mg(6.34 mmol) of lithium chloride were dissolved in 6.3 ml of anhydrousdimethylformamide and the solution was stirred under N₂. The reactionmixture was then treated with 1.02 ml (3.49 mmol) of tri-n-butyl vinyltin over a one-minute period. After about 10 minutes the reaction wasdiluted with H₂ O and (1:1) ethyl acetate/diethyl ether mixture. Theorganic phase was removed and washed (2×) with water. The solvent wasthen removed in vacuo and the crude product residue redissolved into CH₃CN. The CH₃ CN solution was washed (3×) with hexane and concentrated invacuo. Chromatography over silica gel (100% CH₂ Cl₂ to 2% ethylacetate/CH₂ Cl₂ to 5% ethyl acetate/CH₂ Cl₂ gradient elution) provided1.46 g (91% yield) of the title compound.

NMR (300 MHz, CDCl₃): 1.19-1.37 (1H, m); 1.72-1.87 (1H, m); 2.07-2.22(1H, m); 2.57 (1H, doublet of doublets); 3.74-3.85 (1H, m); 4.47 (2H,s); 5.17 (1H, d); 5.30-5.43 (2H, m); 6.77-6.87 (3H, m); 6.93 (7H, t);7.07-7.43 (14H, m).

EXAMPLE 6Benzhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-(2-methyl-1-propene-1-yl)-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5, substitutingtri-n-butyl(2-methyl-1-propene-1-yl)tin as the tin transfer reagent, thetitle compound was produced with the same 1-carba(dethia)ester asstarting material in 76% yield.

NMR (CDCl₃) δ: 1.29-1.45 (4H, m); 1.59 (3H, s); 1.79-1.92 (1H, m);2.09-2.25 (1H, m); 2.26-2.39 (1H, m); 3.82-3.89 (1H, m); 4.49 (2H, s);5.35 (1H, doublet of doublets); 5.75 (1H, s); 6.82-6.89 (2H, m); 6.95(1H, t); 7.04 (1H, d); 7.15-7.39 (13H, m).

EXAMPLE 7

Benzhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-(cis-prop-1-ene-1-yl)-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5, substitutingtri-n-butyl(cis(1-propene-1-yl))tin as the tin transfer reagent andutilizing the same starting material, the title compound was produced in88% yield.

NMR (CDCl₃) δ: 1.40-1.48 (4H, m); 1.90-2.0 (1H, m); 2.26-2.40 (1H, m);2.40-2.52 (1H, m); 2.88-3.98 (1H, m); 4.54 (2H, s); 5.44 (1H, doublet ofdoublets); 5.46-5.60 (1H, m); 6.13 (1H, d); 6.90-6.96 (2H, m); 7.06 (1H,t); 7.11 (1H, d); 7.22-7.48 (13H, m).

    ______________________________________                                                      λ                                                                           ε                                                  ______________________________________                                        U.V.            285    9270.0                                                                 276    9760.0                                                                 269    9120.0                                                 ______________________________________                                    

    ______________________________________                                        Elemental Analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C (%)          73.55   73.30                                                  H (%)          5.79    5.75                                                   N (%)          5.36    5.22                                                   ______________________________________                                    

EXAMPLE 8Benzyhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-(prop-1-yne-1-yl)-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5, substitutingtri-n-butyl(1-propyene-1-yl)tin as the tin transfer reagent andutilizing the same starting material, the title compound was produced in61% yield.

NMR (300 MHz, CDCl₃) δ: 1.32-1.42 (1H, m); 1.82-1.93 (1H, m); 1.96 (3H,s); 2.38-2.60 (2H, m); 3.80-3.88 (1H, m); 4.54 (2H, s); 5.42 (1H,doublet of doublets); 6.88-6.96 (2H, m); 6.98-7.06 (2H, m); 7.18 (1H,d); 7.20-7.54 (12H, m).

U.V.: λ=2.97 nm (ε=16,400)

I.R.: β-lactam C═O: 1772.2 cm⁻¹

EXAMPLE 9Benzhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-methoxymethyl-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5, substitutingtri-n-butyl(methoxymethyl)tin as the tin transfer reagent utilizing thesame starting material, the title compound was produced in 58% yield.

NMR (300 MHz, CDCl₃) δ: 1.13-1.30 (1H, m); 1.59-1.77 (1H, m); 2.07-2.23(1H, m); 2.24-2.33 (1H, m); 3.10 (3H, s); 3.67-3.77 (1H, m); 4.07-4.27(2H, m); 4.43 (2H, s); 5.10-5.37 (1H, m); 6.77-6.93 (4H, m); 7.10-7.47(18H, m).

EXAMPLE 10Benzhydryl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-benzyloxymethyl-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5, substitutingtri-n-butyl(benzyloxymethyl)tin as the tin transfer reagent andutilizing the same starting material, and at a temperature of about65°-70° C., the title compound was produced in 41% yield.

NMR (300 MHz, CDCl₃) δ: 1.15-1.32 (1H, m); 1.70-1.80 (1H, m); 2.13-2.30(1H, m); 2.33-2.47 (1H, m); 3.70-3.80 (1H, m); 4.17-4.53 (6H, m);5.30-5.37 (1H, m); 6.77-7.07 (2H, m); 6.93 (1H, t); 7.13-7.50 (19H, m).

EXAMPLE 11p-Nitrobenzyl-7β-phenoxyacetylamino-1-carba(1-dethia)-3-(t-butyldimethylsilyloxy)methyl-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5, subsitutingtri-n-butyl[(t-butyl dimethylsilyl)oxy]methyl stannane as the tintransfer reagent and utilizing the same starting material, and at atemperature of about 65°-70° C., the title compound was produced in 25%yield.

NMR (300 MHz, CDCl₃) δ: 0.50 (6H, s); 0.87 (9H, s); 1.30-1.45 (1H, m);1.90-2.08 (1H, m); 2.30-2.48 (1H, m); 2.50-2.67 (1H, m); 3.83-3.95 (1H,m); 4.40-4.71 (4H, m); 5.20-5.45 (3H, m); 6.90 (2H, d); 7.00-7.10 (2H,m); 7.23-7.37 (2H, m); 7.60 (2H, d); 8.23 (2H, d).

EXAMPLE 12 Benzhydryl7β-1-carba(1-dethia)-3-(2-methyl-1-propene-1-yl)-3-cephem-4-carboxylate

A 200 mg sample ofbenzyhydryl-7β-D[-t-butoxycarbonylamino)phenylglycylamido]-1-carba(1-dethia)-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylateand 29 mg (0.685 mmol) of lithium chloride and 7.1 mg (0.0274 mmol) ofpalladium dichloride diacetonitrilate was dissolved in 2.74 ml of drydimethylformamide under N₂. The reaction mixture was then treated withtri-n-butyl(2-methyl-1-propene-1-yl)tin. After about 15 minutes thereaction mixture was dilsuted with water and a (1:1) ethylacetate/diethyl ether mixture. The organic phase was washed (3×) withwater and once with brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was then redissolved in CH₃ CNand washed (4×) with hexane. The CH₃ CN solution was concentrated invacuo and chromatographed (6% ethyl acetate/CH₂ Cl₂ to 10% ethylacetate/CH₂ Cl₂ gradient elution) over silica gel to provide 275 mg (79%yield) of the title compound.

NMR (300 MHz, CDCl₃) δ: 0.93-1.10 (1H, m); 1.20-1.43 (13H, m); 1.53-1.66(4H, m); 2.03-2.13 (1H, m); 3.68-3.78 (1H, m); 5.03-5.13 (1H, m); 5.28(1H, doublet of doublets); 5.60 (1H, d); 5.70 (1H, s); 6.43 (1H, broads); 6.80 (1H, s); 7.13-7.38 (16H, m).

EXAMPLE 13 Benzhydryl7β-phenoxyacetylamino-1-carba(1-dethia)-3-(2,2-difluoroethene-1-yl)-3-cephem-4-carboxylate

In a procedure analogous to that utilized in Example 5 (temperature ˜35°C.), substituting tri-n-butyl(2,2-difluoroethene-1-yl)stannane as thetin transfer reagent and utilizing benzhydryl7β-phenoxyacetylamino-1-carba(1-dethia)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylateas starting material, the title compound was produced.

NMR (300 MHz, CD₃ CN) δ: 1.60-1.77 (1H, m); 1.83-1.97 (1H, m); 2.40-2.55(1H, m); 2.63-2.78 (1H, m); 3.80-3.96 (1H, m); 4.53 (2H, s); 5.55 (1H,doublet of doublets); 6.0 (1H, doublet of doublets); 6.83 (1H, s);6.90-7.10 (3H, m); 7.20-7.63 (13H, m).

We claim:
 1. A process for preparing a compound of the formula ##STR16##wherein A is a protected amino group or an acylamino group R(CO)--NH--;R₁ is a carboxy-protecting group or a biologically-labile ester; X issulfur or --CH₂ --; and R₂ is methyl, C₂ -C₆ alkenyl; C₂ -C₆ alkynyl; C₁-C₆ substituted alkyl, C₂ -C₆ substituted alkenyl; C₂ -C₆ substitutedalkynyl; phenyl; substituted phenyl; C₁ -C₆ alkyloxymethyl; phenyl-C₁-C₆ alkyloxymethyl; or tri(C₁ -C₆)alkylsilyloxymethyl; which comprisesreacting a compound of the formula ##STR17## wherein A, X and R₁ are asdefined above, and R₃ is trifluoromethylsulfonyloxy, methanesulfonyloxy,toluenesulfonyloxy, chloro, bromo or iodo; in an inert solvent in thepresence of palladium(O) and, when R₃ is trifluoromethanesulfonyloxy,methanesulfonyloxy or p-toluenesulfonyloxy in the presence of an alkalimetal halide, with a tin transfer reagent of the formula trialkyl(C₁-C₆)alkyl--SN--R₂ or SN(R₂)₄, wherein R₂ has the same meanings asdefined above.
 2. A process according to claim 1, wherein A is aprotected amino group.
 3. A process according to claim 1, wherein A isan acylamino group of the formula R(CO)--NH-- and R is hydrogen; C₁ -C₆alkyl, C₁ -C₆ alkyl substituted by cyano, carboxy, halogen, amino, C₁-C₄ alkoxy, C₁ -C₄ alkylthio, or trifluoromethylthio;a phenyl orsubstituted phenyl group represented by the formula ##STR18## wherein aand a' independently are hydrogen, halogen, hydroxy, C₁ -C₄ alkoxy, C₁-C₄ alkanoyloxy, C₁ -C₄ alkyl, C₁ -C₄ alkylthio, amino, mono- or di(C₁-C₄ alkyl)amino, C₁ -C₄ alkanoylamino, C₁ -C₄ alkylsulfonylamino,carboxy, carbamoyl, hydroxymethyl, aminomethyl or carboxymethyl; a grouprepresented by the formula ##STR19## wherein a and a' have the samemeanings as defined above, Z is O or S, and m is 0 or 1; aheteroarylmethyl group represented by the formula

    R.sup.1 --CH.sub.2 --

wherein R¹ is thienyl, furyl, benzothienyl, benzofuryl, indolyl,triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,and such heteroaryl groups substituted by amino, hydroxy, halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylsulfonylamino; a substitutedmethyl group represented by the formula ##STR20## wherein R² iscyclohex-1,4-dienyl, or a phenyl group or substituted phenyl grouprepresented by the formula ##STR21## wherein a and a' have the abovedefined meanings, or R² is R¹ as defined above, and Q is hydroxy, C₁ -C₄alkanoyloxy, carboxy, sulfo, or amino; or R is a keto group or anoximino-substituted group represented by the formulae ##STR22## whereinR³ is R¹ or R² as defined above and R⁴ is hydrogen, C₁ -C₄ alkyl, or acarboxy-substituted alkyl or cycloalkyl group represented by the formula##STR23## wherein b and b' independently are hydrogen, or C₁ -C₃ alkyl,and b and b' when taken together with the carbon to which they arebonded form a 3- to 6-membered carbocyclic ring, and R⁵ is hydroxy, C₁-C₄ alkoxy, amino, C₁ -C₄ alkylamino or di(C₁ -C₄ alkyl)amino and n is 0or
 1. 4. A process according to claim 2, wherein the protected aminogroup is represented by the formula ##STR24## wherein R^(o) ₁ is C₁ -C₄alkyl, C₃ -C₇ cycloalkyl, benzyl, nitrobenzyl, halobenzyl ormethoxybenzyl.
 5. A process according to claim 4 wherein the protectedamino group is benzyloxycarbonylamino, p-nitrobenzyloxyamino ort-butyloxycarbonylamino.
 6. A process according to claim 3, wherein theacylamino group R(CO)--NH-- is phenoxyacetylamino or phenylacetylamino.7. A process according to claim 1, wherein R₁ is diphenylmethyl or4-nitrobenzyl.
 8. A process according to claim 1, wherein X is sulfur.9. A process according to claim 1, wherein X is --CH₂ --.
 10. A processaccording to claim 1, wherein R₂ is C₂ to C₆ alkenyl.
 11. A processaccording to claim 10, wherein R₂ is C₃ to C₆ alkenyl.
 12. A processaccording to claim 11, wherein R₂ is (Z)-3,3,3-trifluoro-1-propene-1-ylor (Z)-1-propene-1-yl.
 13. A process according to claim 12, wherein X isS and R₂ is (Z)-1-propene-1-yl.
 14. A process according to claim 1,wherein R₃ is trifluoromethanesulfonyloxy, bromo or iodo.
 15. A processaccording to claim 1, wherein R₃ is trifluoromethanesulfonyloxy,methanesulfonyloxy or p-toluenesulfonyloxy and the alkali metal halideis lithium chloride or lithium bromide.
 16. A process according to claim1, wherein the Pd(O) is generated in situ from palladium dichloridediacetonitrilate.